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BP: Fachverband Biologische Physik

BP 19: Membranes and Vesicles II

BP 19.1: Vortrag

Mittwoch, 19. März 2025, 09:30–09:45, H46

Atomistic Insights into pH-Dependent Structural Transitions in Lipid Mesophases: A Combined MD/SAXS Approach — •Akhil Sudarsan¹, Julian Philipp², Joachim Rädler², and Nadine Schwierz¹ — ¹University of Augsburg, Augsburg, Germany — ²Ludwig Maximilians-University, Munich, Germany

Lipid nanoparticles (LNPs) are crucial delivery vehicles for mRNA-based therapeutics, enabling the encapsulation and release of negatively charged nucleic acids through ionizable lipids that exhibit pH-dependent fusogenic activity. This study investigates ionizable DLin-MC3-DMA (MC3) lipid/cholesterol mesophases that mimic the core structure of LNPs, focusing on the inverse hexagonal (H_II) and inverse micellar (L_II) phases, both featuring an internal water domain surrounded by ionizable lipids. By combining experimental SAXS data and molecular dynamics (MD) simulations, we show that the L_II phase, which is stable at higher pH, transitions to H_II at lower pH. We also calculate the water content of the simulated core phases through comparison with scattering data and elucidate the distribution of lipids in these mesophases. We further developed an approach to compute scattering profiles directly from MD simulations, which corrects for artifacts arising from periodic boundary conditions, enabling direct, model-free comparisons between experimental and simulated data enhancing the reliability of the structural interpretations. In summary, integrating SAXS experiments and MD simulations offer molecular insights into the dynamic behaviour and pH-dependent structural transitions of ionizable lipid mesophases.

Keywords: molecular dynamics; lipid nanoparticles; phase transition; x-ray scattering; ionizable lipids